Project Summary Creatine transporter deficiency (CTD) is a metabolic disorder that results in a lack of cerebral creatine (Cr). The primary phenotype of CTD is intellectual disability, aphasia, and epilepsy. There are no treatments available for CTD. In order to understand CTD, we have developed Creatine transporter knockout (Slc6a8-/y) mice that have significant cognitive deficits. The main function of Cr is to replenish ATP levels during times of high energy demand. Compared with Slc6a8+/y mice, Slc6a8-/y mice have reduced ATP levels along with increases in whole-body and cellular metabolism. This phenotype makes the Slc6a8-/y mouse an ideal model in which to test potential therapies. The long-term goal of this research is to develop safe and effective treatments for CTD. While the primary treatment options involve restoring Cr function, the possibility of alternative/adjunctive therapies should be explored. If the ATP deficits in Slc6a8-/y mice underlie the cognitive deficits, it stands to reason that increasing ATP levels should restore cognitive function. Ketone bodies (KB) are energetically favorable mitochondrial substrates, producing more ATP per molecule than glucose. Blood and brain KB can be elevated using a ketogenic diet, which is high in fat and low in carbohydrates. The KD increases ATP levels in other mouse models with brain ATP reductions. The hypothesis of this study is that a KD is sufficient to ameliorate the cognitive and metabolic deficits observed in Slc6a8-/y mice. In order to test this hypothesis, 2 specific aims have been devised. In specific aim 1, effects of a KD will be evaluated. The diet will be initiated in young mice in order to model early age treatment in humans. Following 6 weeks on the diet, spatial learning and memory, novel object recognition, and conditioned fear will be evaluated. Brain ATP levels will be measured following testing. In specific aim 2, a group of Slc6a8-/y mice will be treated with MCT oil to increase ketone body levels without the cardiovascular and growth-related concerns that often surround a KD. Neuronal morphology will be evaluated in both groups of mice. Taken together, these studies will provide a significant advancement in the treatment and understanding of CTD and the role of Cr in the brain.